What is the significance of considering cerebrospinal fluid (CSF) anti-myelin oligodendrocyte glycoprotein (MOG) testing in patients with suspected demyelinating diseases?

CSF Anti-MOG Testing: The 2025 ECTRIMS Perspective

While the 2018 international consensus guidelines established that serum is the preferred specimen for MOG-IgG testing because the antibody is produced extrathecally, emerging evidence suggests CSF testing may have limited diagnostic utility in highly selected seronegative cases—though this remains controversial and should be approached with extreme caution. 1, 2

The Core Recommendation: Serum First, Always

Serum MOG-IgG testing using cell-based assay with full-length human MOG remains the gold standard diagnostic approach. 1, 2 The international consensus is unequivocal that MOG-IgG is produced mostly extrathecally, making serum the specimen of choice. 2

When CSF Testing Might Be Considered (Rare Scenarios)

The 2018 guidelines acknowledge CSF may be "potentially helpful in rare, selected cases," though they do not specify which cases. 2 Recent research provides some clarity:

• CSF-restricted MOG-IgG has extremely low sensitivity (2.63%) and poor positive predictive value (1.97%) in seronegative patients. 3 In a large referral cohort, only 7 of 1,016 (0.7%) seronegative patients had CSF-restricted MOG-IgG. 3

• Among those 7 CSF-only positive cases, 4 had confirmed alternate diagnoses (3 with MS, 1 with CNS vasculitis), meaning the majority were false positives. 3 Only 3 had longitudinally extensive transverse myelitis consistent with MOGAD. 3

• A separate study found CSF MOG-IgG in 3 of 80 seronegative cases (4% overall, 7% excluding MS patients)—2 with NMOSD and 1 with ADEM. 4 This suggests CSF testing might identify a small subset of true MOGAD cases missed by serum testing. 4

Critical Technical Considerations

If CSF testing is pursued despite low yield, specific handling is essential:

• Ship CSF at 4°C or on dry ice if samples will not arrive within 1-2 days. 2
• Test CSF undiluted and at 1:2 dilution with further titrations if positive. 4
• Use anti-IgG-Fc secondary antibodies to confirm exclusive presence of MOG-IgG (not IgM). 4
• Recognize that CSF MOG-IgG positivity in serum-positive patients is common (8 of 13 cases in one study), but this adds no diagnostic value. 4

The Major Pitfall: CSF-Only Positivity as a Red Flag

The 2018 guidelines originally listed "MOG-IgG positivity in CSF but not in serum" as a red flag suggesting false positivity. 1 However, more recent data suggests this may be overly restrictive, as rare true MOGAD cases can present with CSF-restricted antibodies. 2, 4

The critical clinical decision point: CSF-only MOG-IgG positivity should prompt extreme skepticism and mandate:

• Retesting with an alternative cell-based assay methodology. 1
• Rigorous evaluation for alternate diagnoses, particularly MS (check for Dawson's fingers, periventricular lesions, oligoclonal bands). 1, 3
• Confirmation that clinical and radiological features are truly consistent with MOGAD (longitudinally extensive lesions, optic nerve involvement, absence of progressive course). 1, 3

When to Retest: Timing Matters

MOG-IgG concentrations fluctuate with disease activity and treatment status. 1, 2 If initial serum testing is negative but clinical suspicion remains high:

• Retest during acute attacks when titers are highest. 1, 2
• Retest during treatment-free intervals (immunosuppression lowers titers). 1, 2
• Retest 1-3 months after plasma exchange or IVIG, as these treatments can cause false-negative results. 1, 2

The Bottom Line for Clinical Practice

In real-world practice, CSF MOG-IgG testing should be reserved for the exceptional patient who:

1. Has serum MOG-IgG testing that is negative on at least two occasions (including during acute attack and off immunosuppression). 2, 3
2. Has clinical and radiological features highly consistent with MOGAD (longitudinally extensive transverse myelitis, bilateral optic neuritis, absence of MS-typical features). 1, 3
3. Has no oligoclonal bands and no MRZ reaction (which would favor MS). 1
4. Has CSF findings compatible with MOGAD (possible neutrophilic pleocytosis, elevated protein). 1, 2

Even in this scenario, a positive CSF result requires confirmation with alternative methodology and expert consultation before making treatment decisions. 1, 3 The risk of misdiagnosing MS as MOGAD based on CSF-only positivity is substantial, with potentially harmful treatment implications (avoiding MS therapies that are needed, or using immunosuppression that may be inappropriate). 2, 3